The liver is unique in that it traps and kills activated CD8+ T cells. This results in the development of hepatitis, which is not driven by the direct recognition of antigen on hepatocytes by CD8+ T cells, but by an indirect or bystander mechanism. Our preliminary studies using a respiratory virus (influenza A) to drive the expansion and accumulation of antigen-specific CD8+ T cells in the liver indicate that this bystander hepatitis requires the presence of Kupffer cells (KCs). The significance of this work is twofold: First, we show that bystander hepatitis occurs in patients as well as mice infected with influenza and that hepatitis may be a general consequence of the hepatic clearance of large numbers of CD8+ T cells generated during the course of virus infections. Secondly, our analysis of bystander hepatitis has revealed the importance of KCs in mediating the deletion of intrahepatic CD8+ T cells as well as inducing the associated liver damage. We have recently developed a model of hepatotrophic viral infection using an Adeno-Associated Virus (AAV) encoding the SIINFEKL antigen recognized by CD8+ T cells from the OT-1 transgenic mouse. Using this AAV-OVA and an influenza model, we propose experiments to test the hypothesis that KC activation (mediated through interferon-g and TNFa) is critical for both the deletion of CD8+ T cells and the generation of hepatitis (Aim 1). Furthermore, we postulate that KC-mediated killing of anti-viral cytotoxic T lymphocytes (CTLs) inhibits the antiviral CTL response (Aim 2) and that KC-mediated bystander effect contributes to liver damage even in the context of an intrahepatic infection (Aim 3). Finally, we propose to test selective inhibition of KC activity as a novel therapy to improve viral clearance and decrease liver damage in our AAV- OVA model of hepatotrophic virus infection. These experiments will shed light on how KCs affect CTL-dependent immune responses in the liver and may clarify the mechanism through which hepatotrophic pathogens such as HCV evade immune clearance and establish chronic infections.